The present invention relates to a method for constructing an implant by placement of a paste comprising a stimuli sensitive polymer solution carrying a biocompatible ceramic component which hardens under physiological conditions to form a solid implant. The implant may also include a therapeutic agent or a radioisotope.
Many researchers have experimented with drug delivery vehicles based on the use of controlled release implant materials. Others have sought to provide improved implants for filling in tissue losses from age or trauma, to hard or soft tissues. Calcium phosphate pastes have been suggested as bone and dental fillers. Gels have been used as control release devices and as fillers. Representative studies are discussed below.
In U.S. Pat. No. 4,188,373, certain polyols are used in aqueous compositions to provide thermally gelling aqueous systems. In these systems, the sol-gel transition temperature can be changed by manipulating the concentration of polymer. In U.S. Pat. Nos. 4,474,751; ""752; ""753; and 4,478,822 drug delivery systems are described which utilize thermosetting gels. In these systems, both the gel transition temperature and/or the rigidity of the gel can be modified by adjustment of the pH and/or the ionic strength, as well as by the concentration of the polymer. U.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760, and 4,911,926 also disclose gels that deliver pharmaceutical compositions.
In U.S. Pat. No. 4,895,724, compositions are disclosed for the controlled release of pharmacological macromolecular compounds contained in a matrix of chitosan. Chitosan can be cross-linked utilizing aldehydes, epichlorohydrin, benzoquinone, etc. In U.S. Pat. No. 4,795,642, discloses gelatin-encapsulated, controlled-release pharmaceutical compositions, wherein the gelatin encloses a solid matrix formed by the cation-assisted gelation of a liquid filling composition incorporating a vegetable gum together with a pharmaceutically-active compound. The vegetable gums are disclosed as polysaccharide gums such as alginates which can be gelled utilizing a cationic gelling agent such as an alkaline earth metal cation.
Osmotic drug delivery systems are disclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chamber compartment for holding osmotic agents, adjuvants, enzymes, drugs, pro-drugs, pesticides, and the like. These materials are enclosed by semipermeable membranes so as to allow the fluids within the chambers to diffuse into the environment into which the osmotic drug delivery system is in contact. U.S. Pat. No. 5,587,175 teaches a process for forming a protective corneal shield or an ablatable corneal shield or mask in situ comprising administering to the eye of a mammal an aqueous composition capable of being gelled in situ to produce an hyper osmotic, hypo osmotic, or iso osmotic aqueous gel having a controlled pH, said aqueous composition, including at least one film forming polymer; and gelling said film forming polymer in situ to form said protective corneal shield or ablatable corneal shield or mask.
U.S. Pat. No. 3,949,073 discloses injectable atelocollagen solutions which precipitate at body temperature, thus leading to the formation of fibers which remain at the injection site whereas the excipient is progressively resorbed. U.S. Pat. No. 5,658,593 in one embodiment provides micro capsules based on atelocollagen optionally mixed with a glycosaminoglycan such as chondroitin-4-sulfate, the micro capsules containing granules of hydroxyapatite in suspension in a viscous bio compatible carrier solution of a gel of atelocollagen optionally mixed with a glycosaminoglycan, in particular chondroitin-4-sulfate, for use as a filler material in forming injectable implants.
U.S. Pat. No. 5,626,861 teaches a method for the fabrication of three-dimensional macro porous polymer matrices for use as bone graft or implant material was developed. The composites are formed from a mixture of biodegradable, bio compatible polymer and hydroxyapatite (HA), a particulate calcium phosphate ceramic. The method leaves irregular pores in the composite between 100 and 250 microns in size by formation of a solid gel comprising a soluble material and dissolving the material to form voids in the gel. In a preferred embodiment, implants are composed of a 50:50 poly(lactide-co-glycolide) (PLGA) polymer and reinforced by hydroxyapatite. Mechanical and histological analysis showed the matrix fabricated by this method to be structurally and mechanically similar to cancellous bone. Prior to degradation, pure polymer specimens exhibited an elastic modulus of 293 MPa and specimens which were 50% HA by weight exhibited a modulus of 1459 MPa. After six weeks of degradation under physiological conditions, the reinforcing effect of ceramic loading had diminished. Modulus of polymer matrices at all HA load levels had decreased sharply to approximately 10 MPa. Mean macro- and micro pore diameters of the polymer specimens were 100 mu m and 20 mu m respectively and remained constant throughout degradation. The implants are hardened, leached and then implanted into the subject where they are slowly degraded by natural bodily action over a period of time. The implant size and shape must be predetermined and thus may not perfectly fit the site to be repaired.
B. R. Constantz, et als, 1995, Skeletal Repair by in Situ Formation of the Mineral Phase of Bone, Science, 267:1796-1799. Discloses a process for the surgical implantation of a paste that hardens in minutes under physiological conditions. The mixture comprises a mixture of calcium phosphates and sodium phosphate, and hardens due to the crystallization of dahlite, not mediated by a stimulus setting gel. The mixture hardens regardless of whether it is placed in the body. The paste is a hydroxyapatite precursor and does not include gel components. 
B. Flautre, et als, 1996, Evaluation of Hydroxyapatite Powder Coated with Collagen as an Injectable Bone Substitute: Microscopic Study in Rabbit, J. Materials Science:Materials in Medicine, 7:63-67, discloses an injectable mix of hydroxyapatite and collagen but there is no disclosure of providing a stimulus response setting material. The group uses HA and atecollegen and chondrotin-4-sulfate formulated as micro spheres, similar to the patents discussed above. There is no provision for a gel which forms in response to a stimulus provided by exposure to the environment of the body, and there is no provision for differential loss of materials to provide a porous matrix. A further study by the same group, G. Pasquier, et als, 1996, Injectable Percutaneous Bone Biomaterials: an Experimental Study in a Rabbit Model, J. Materials Science:Materials in Medicine, 7:683-690, discloses mixtures comprising an orthopaedic acrylic cement (polymethylmethacrylate (xe2x80x9cPMMAxe2x80x9d)) and HA as well as HA and collagen. The PMMA was used as a reference bio-inert material. There is no disclosure of a stimulus setting gel for producing a composite which only hardens in response to a stimulus supplied by the body.
M. Ito, et als, 1994, Experimental Development of a Chitosan-bonded xcex2-Tricalcium Phosphate Bone Filling Paste, Bio-Medical Materials and Eng., 4:439-499, discloses a composite of chitosan and tricalcium phosphate containing alkaline oxides of calcium, magnesium or zinc, which provided the conditions to produce setting. Again the material hardens without regard to stimulus supplied from the body. A similar study is reported by M. Takechi, et als, 1996, Non-decay Type Fast-setting Calcium Phosphate Cement Using Chitosan, J. Materials Science:Materials in Medicine, 7:317-322. Takechi uses sodium alginate or chitosan as a water insoluble gel to protect calcium phosphate cements from decay during setting under physiological conditions. In these materials the cements set as they normally do and the gel forms in response to the calcium provided by the cement. Again there is no gel formation in response to a physiological stimulus for the composite material.
There is a continuing and long felt need for alternative implant materials for the treatment of damage to bony tissues by injury or disease. The art has not heretofore provided a fluid or shapeable implant material which comprises both a bone growth supporting matrix such as a ceramic matrix, and a stimulus sensitive gel which can be shaped to fill an injury site and then hardens to support the injured tissue during healing. The art has not heretofore provided a polymer/ceramic composite suitable for use in bone repair wherein a stimuli sensitive gel is used as a fluid carrier to place a ceramic matrix into a damaged bony tissue wherein the gel hardens in response to a physiological condition such as temperature, pH, ionic strength and the like in the presence of the ceramic.
The present invention provides a composition which comprises a polymer or polymer solution that forms a gel under controlled parameters and a ceramic matrix, the composition being fluid under non-physiological conditions and non fluid under physiological conditions. Polymers may be resorbable or nonresorbable, natural or synthetic and the solution aqueous or non aqueous. Preferred polymers are poly-saccharides, random copolymers of (meth)acrylamide derivatives with hydrophillic comonomers, or polyamino acids, however any polymer or polymer solution that is biologically compatible and that is fluid under nonphysiological conditions and increases in viscosity under physiological conditions is suitable. As used in this application, physiological conditions means conditions normally found in a mammalian body such as pH in the range of 4 to 9, ionic strength of around 0.15 or temperature in the range of 35-40xc2x0 C. Stimuli sensitive gel means a natural or synthetic polymer that increases in viscosity, gels or crosslinks in response to a stimulus such as a change in temperature, pH, ionic strength, light or the like. In contrast to the rigid composites synthetic grafts of the prior art, the compositions of the present invention may be injected at a trauma site, such as a fracture and shaped to fill any voids present, forming and in situ splint and scaffold for the growth of new bone. The composite may also serve as a controlled release device for a therapeutic agent such as a bone growth factor, an antibiotic, a chemotherapy drug, or a cytokine. The composites may include bone morphogenic proteins or other osteoconductive agents. Preferably the composites are formed in such a manner that the final solid implant is porous with macroscopic pores, preferably on the order of 100 to 200 microns in cross section. In an alternative embodiment a near net shape forming composition is employed wherein the polymer is a bio compatible, shear thinning polymer that forms a gel under ambient pressure and a ceramic component carried therein. The shear thinning polymer is one in which the polymer viscosity decreases in response to a stimulus such as ultrasonic vibration or injection.
Alternatively the invention may be viewed as a method of forming a solid implant in a mammalian body which comprises mixing a gel forming component with a ceramic forming component to provide a fluid mixture, placing the fluid mixture into a mammalian body wherein the fluid mixture gels after placement in the mammalian body in response to a stimulus provided by conditions present or induced in the mammalian body. Conditions present in the mammalian body includes normal body temperature, ionic strength, pH and the like. Conditions that can be induced in the body include ultrasonic vibration, externally applied magnetic fields, irradiation from a radiation source or light or other electromagnetic radiation. Preferably the fluid mixture comprises a gel forming polymer, a calcium phosphate ceramic, and a soluble material which will produce voids in the final implant, the voids having an average cross section in the range of 100 to 200 microns. The soluble material is preferably a second polymer which degrades or dissolves relatively rapidly under physiological conditions. Especially preferred polymers dissolve by enzymatic action leaving non toxic, non irritating residues.